To our knowledge, this case of SPB showing dual expression of the kappa and lambda light chains is the first of its kind to have been reported. Normal plasma cells differentiate from B-cells and produce Ig. B-cells can rearrange their Ig genes to recognize a huge variety of different antigens. Ig is normally composed of one heavy and one light chain. There are five types of IgH – IgM, IgG, IgA, IgD and IgE produced by a single gene – and two types of IgL – kappa and lambda produced by two distinct genes. The IgH, IgL kappa, and IgL lambda gene loci are located on chromosome 14, 2, and 22, respectively. If the IgH and one of the IgL genes are rearranged successfully, the other allele of the Ig gene is excluded to maintain the antigen specificity of the B-cell, a phenomenon known as “allelic exclusion”. In this way, a single B-cell expresses the rearranged IgH and the either IgL genes transcribed from only one allele each, with the other 4 alleles remaining in the germline configuration. Normal B-cells first undergo IgH rearrangement, followed by IgL kappa rearrangement. If a productive IgL kappa rearrangement occurs, the IgL lambda gene never rearranges. If IgL kappa rearrangement is nonproductive for both alleles, the IgL kappa locus is inactivated by deletion and IgL lambda rearrangement occurs.8,9 This mechanism of expressing either IgL kappa or lambda genes is called “isotypic exclusion”, and thus B-cells (or plasma cells) express one type of light chain, but not both.10 “Isotypic exclusion” of IgL is not fully understood, although some hypotheses have been proposed on the basis of experimental studies. Inactivation of IgL kappa is accomplished by recombination activating gene (RAG)-mediated joining of the non-coding recombining sequence (RS). The RS is the IgL kappa-deleting element in humans, located ~25 kilobases downstream of the constant region of IgL kappa (C-kappa).11,12 RS recombination leads to deletion of the C-kappa exon and silencing of the IgL kappa allele, and it is also known that RS recombination promotes the formation of B cells which express IgL lambda chain.12–14 However, Diaw et al. reported a mouse-origin plasmacytoma that produced both IgL kappa and lambda, and using micro-manipulation and RT-PCR confirmed that both were expressed simultaneously in a single cell.18 This suggests that in some plasma cell neoplasms both kappa and lambda light chains may exist in a single plasma cell. Furthermore, few cases of PCM showing dual expression of IgL have been reported. The majority of such cases have tended to show a high incidence of complex cytogenetic or FISH abnormalities, suggesting involvement of the light chain genes, subsequent isotypic exclusion error, and dual light chain expression.15–17 Unfortunately, as no investigation of chromosome abnormalities was undertaken in the present case, any genetic dysfunction related to isotypic exclusion remained unclear. On the other hand, Shi et al. subjected human peripheral B-cells to single-cell sequencing and found that more than one antibody was produced in some individual B-cells, albeit accounting for a small proportion of the total (about 10%).19 This unprecedented finding appears to cast doubt on the traditional “one cell – one antibody” paradigm and suggested that dual expression of kappa and lambda light chain can occur in normal conditions and might be the origin of the dual IgL expression neoplasm. However, due to the limited number of cases, further investigation is needed to elucidate the mechanism of tumor co-expression of kappa and lambda light chains.
The findings in the present case invite speculation as to how both the kappa and lambda light chains can exist in a single neoplastic plasma cell. Two hypotheses to explain this have been suggested: (1) two types of light chain are expressed in the same antibody, (2) two types of antibodies constructed by each of the kappa and lambda light chains are present in the same plasma cell. In the present case, we detected coexpression of both IgLs in the neoplastic cells by flow cytometry, immunohistochemistry and in situ hybridization (ISH) targeting IgL mRNA, but none of the results offered any suggestion about either hypothesis. There is no way to test these hypothesis at this stage, and further analysis is needed.